First Geriatric Cardiology Division, Chinese PLA General Hospital, Beijing 100853, PR China.
Int J Mol Med. 2012 Oct;30(4):765-74. doi: 10.3892/ijmm.2012.1054. Epub 2012 Jul 4.
The aim of this study was to identify the molecular mechanisms and biological pathways associated with the anticancer effects of atorvastatin. For this purpose, we conducted cell-based microarray and bioinformatic analyses to determine the effect of atorvastatin exposure on endothelial cell response. The results of bioinformatic analysis performed using the Connectivity Map (cMap) to examine the atorvastatin-induced changes in gene expression in the human umbilical vein endothelial cell line, EA.hy926, indicated that treatment with 10 µM of atorvastatin for 24 h upregulated the expression of 295 genes and downregulated the expression of 354 genes by 2-fold compared to the control treatment. The gene set enrichment analysis (GSEA), the Database for Annotation, Visualization and Integrated Discovery (DAVID) pathway analysis, and Gene Ontology (GO) analysis of differentially expressed genes revealed that Kruppel-like factors (KLFs) and cell cycle-related genes were the genes most significantly affected by atorvastatin treatment. The upregulation of KLFs and the downregulation of the cell cycle-related genes, including cyclin (CCN)A2, CCNE2, CCNB1 and CCNB2, were validated by real-time polymerase chain reaction (RT-PCR). A comparison of the gene expression profile of atorvastatin-treated cells with that of the control cells and with that of 6,100 compounds in the cMap database revealed that the profile of atorvastatin-treated cells was highly similar to that of histone deacetylase (HDAC) inhibitor-treated cells. Therefore, these results suggest that atorvastatin acts as an HDAC, a G1/S (start) and a G2/M (mitosis) cell cycle inhibitor. These findings provide evidence of the feasibility of the use of atorvastatin as an anticancer drug.
本研究旨在确定与阿托伐他汀抗癌作用相关的分子机制和生物学途径。为此，我们进行了基于细胞的微阵列和生物信息学分析，以确定阿托伐他汀暴露对内皮细胞反应的影响。使用 Connectivity Map (cMap) 进行的生物信息学分析的结果表明，阿托伐他汀处理人脐静脉内皮细胞系 EA.hy926 24 小时后，与对照处理相比，有 295 个基因的表达上调，354 个基因的表达下调了 2 倍。差异表达基因的基因集富集分析 (GSEA)、Database for Annotation, Visualization and Integrated Discovery (DAVID) 通路分析和 Gene Ontology (GO) 分析表明，Krüppel-like factors (KLFs) 和细胞周期相关基因是受阿托伐他汀处理影响最显著的基因。KLFs 的上调和细胞周期相关基因的下调，包括 cyclin (CCN)A2、CCNE2、CCNB1 和 CCNB2，通过实时聚合酶链反应 (RT-PCR) 得到验证。阿托伐他汀处理细胞的基因表达谱与对照细胞和 cMap 数据库中 6100 种化合物的基因表达谱进行比较，结果表明阿托伐他汀处理细胞的基因表达谱与组蛋白去乙酰化酶 (HDAC) 抑制剂处理细胞的基因表达谱高度相似。因此，这些结果表明阿托伐他汀作为一种 HDAC、G1/S（起始）和 G2/M（有丝分裂）细胞周期抑制剂发挥作用。这些发现为使用阿托伐他汀作为抗癌药物的可行性提供了证据。
